The development of chronobiological knowledge, as described for example by Lemmer in Journal of Controlled Release 16 (1991) 63-74 and Lemmer, European Heart Journal (1998) 19 (Supplement C) C50-C58, has led to an interest in chronotherapeutics, which is the release of a drug in the body in synchronisation with the biological rhythm. The role of circadian rhythms in the function of the body and hence the therapeutic needs have in particular been investigated. Cardiovascular activity, pulmonary, hepatic, gastrointestinal and renal functions are all known to follow circadian rhythms, and for instance, gastric motility, gastric pH, and enzymatic secretion vary during the day. Given that hepatic and renal activity also vary, then it follows that absorption, metabolism and excretion can be expected to follow the same pattern. The therapeutic and toxic effect of drugs can therefore display a significant variation during the course of a day. It is preferable that the biological rhythms be taken into consideration when a new drug delivery system is developed.
The goal is to design a system that allows drug delivery to be decoupled from the act of drug administration and to be synchronised with the biological rhythm, in accordance with chronotherapeutics. Drug administration can then occur at a convenient time, rather than at a time dictated by drug delivery.
To address such needs, a triggered, pulsed or programmed drug delivery system is more suitable, rather than a conventional normal release or controlled release dosage form. This system might provide one or more of the following advantages:                produce maximum benefits with minimum side effects;        avoid drug tolerance;        overcome a saturable first pass loss via the gastrointestinal tract;        reduce dose frequency and dose level and thus increases patient compliance;        deliver the drug at the time most needed.        
Some delayed release dosage forms are already known. Mechanical disruption of a delayed release coat provides one mechanism for a delayed release system. In one proposal, a formulation is made comprising a core containing a drug and a swelling agent, coated with a water-insoluble but permeable polymer, see Ueda et al. in Journal of Drug Targetting, 1994, 2, 35-44. After the device is orally administered, water permeates into the core, which hydrates and swells. The stress caused by the swelling ruptures the coating to enable drug release. In a variation different fillers were used, including an effervescent agent, which were filled into capsules and coated with water-insoluble polymers.
Santus G and Baker R, 1995, Journal of Controlled Release 35 (1995) 1 reviewed the literature using the concept of osmotic pressure in controlling the drug release. Single unit devices such as tablets, hard and soft capsules and other mechanical osmotic pumps were reviewed and analysed. The authors concluded that osmotic systems could be used effectively to determine the time and the rate of the drug release. Thus, the swelling agent in the core is replaced with an osmotic agent and the core is coated with a semi-permeable membrane. Osmotic pressure thus exerts a stress on the membrane, rupturing it and so resulting in a rapid release of the drug. This technology is suitable for devices having a low surface area/volume ratio such as single unit dosage forms for example tablets.
Another type of delivery system relies on hydration or erosion. A notable example consists of a water insoluble capsule filled with a drug plugged with a hydrogel and covered with a water-soluble cap. After the capsule is orally administered the cap dissolves and the hydrogel plug becomes fully hydrated after a certain time and is expelled, thereby permitting a rapid and complete release of the drug. Such a device referred to as the Pulsincap™ device was disclosed by Scherer DDS in 1991, see Pharma. J., Vol. 247, 138. An alternative pulsatile drug release system is described by Krogel and Bodmeier in Pharmaceutical Research, 1998, 15, 474, using an erodible plug formed by compression or from a melt as a closure to an impermeable capsule body.
Yet another delivery system based on hydration and erosion is that described by Pozzi et al. in Journal of Controlled Release, 1994, 31, 99-108. The device is a solid core coated with a hydrophobic-surfactant layer, applied as an aqueous dispersion, to which a hydrosoluble polymer is added to improve adhesion to the core. The coating rehydrates and redisperses in an aqueous environment in a time proportional to the thickness of the film. Thus the coat has been designed to be completely removed after a pre-determined lag time depending on the coat thickness. The different physiological and chemical environment through the gastrointestinal tract are not expected to alter significantly the releasing time.
A further delayed release system comprises a solid core of drug an organic acid such as succinic acid and coated with a thick coat of Eudragit RS, see Narisawa et al, 1994, Pharm. Res. Vol. 11, 111 and Narisawa et al. International Journal of Pharmaceutics 148 (1997) 85-91. Eudragit RS is a copolymer synthesised from acrylic and methacrylic acid esters with a low level of quaternary ammonium groups. The film formed by this polymer is water insoluble with low permeability. On full hydration, water gradually penetrates the membrane into the core and dissolves the organic acid. The resulting polymer/acid interaction induces a structural change in the coating film, increasing permeability, which enhances the drug release.
A similar approach to the above is described in Ishibashi et al. International Journal of Pharmaceutics, 168 (1998) 31-40. This device comprises a blend of drug and organic acid made into solid cores which are filled into gelatin capsules. The capsule is coated with three different polymeric layers; an inner layer consisting of cationic polymer dissolving in acidic fluid, a water-soluble intermediate layer, and an outer layer consisting of enteric materials dissolving at pH above 5. The intermediate layer serves to prevent direct contact between the inner and outer layers. The predicted performance of this product is that drug release is prevented in the stomach by the outer polymeric layer, after gastric emptying the outer and intermediate layers quickly dissolve but the inner polymeric layer remains to prevent drug release in the intestine, and then when the pH inside the capsule gradually decreases with dissolution of the organic acid and the inner polymeric layer is dissolved by the acidic fluid, the drug content is quickly released.
One simple approach to delaying the release of drug relies solely on the enteric behaviour of some polymers whereby the delay is dependent upon gastric residence time. Devices of this kind, which may comprise tablets capsules, spheroids and beads, can be coated with polymers that dissolve only in a medium of pH 5 or higher. The coated core will survive the low pH in the stomach and release its contents rapidly in the alkaline environment of the upper part of the intestine.
Systemic delivery of therapeutic peptides and proteins via the colon may be achieved way from a delayed release dosage form. Recently, the unprecedented rapid development of biotechnology and genetic engineering has resulted in the availability of a significant number of peptides and proteins at a reasonable price. Colonic delivery has attracted much interest, see for example Banga and Chien in International Journal of Pharmaceutics, 48 (1988) 15-50; Fix in Pharmaceutical Research, 13 (1996) 1760; and Ziv et al., Journal of Pharmaceutical Sciences, 83 (1994) 792. Among several routes intensively studied is colonic delivery because of the low activity of pancreatic erzymes, the reduced brushborder membrane peptidase activity and the avoidance of liver first pass.
The available technologies for delayed release pharmaceutical compositions have a number of disadvantages. The development of a system which is independent of the physiological condition of the gastrointestinal tract, unaffected by fed and fast condition of the patients offers a considerable challenge.
An object of the present invention is to provide a pharmaceutical composition which is capable of delayed and then rapid release of the active ingredient.